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This study aimed to investigate the effects of signal transducer and activators of transcription 3 (STAT3) phosphorylation on the function of decidual regulatory T (Treg) cells in unexplained recurrent spontaneous abortion (URSA) patients and to explore the mechanism of STAT3 in URSA. Treg cells were sorted out from the decidual tissue by magnetic beads. The inhibitor Stattic was utilized to alter the phosphorylation status of STAT3 (pSTAT3) in Treg cells. The proliferation and suppression of Treg cell were detected by flow cytometry, real-time quantitative fluorescent PCR and ELISA. The factors that caused the hyperphosphorylation of Treg cells were detected. Our results showed that the proportion of pSTAT3 cells in the decidual Treg cells of URSA patients was significantly increased. pSTAT3 inhibited the proliferation of Treg cells by downregulating the expression of STAT5 and Foxp3 and increased the number of responder T cells. pSTAT3 decreased the secretion of TGF-β1 and IL-10 in Treg cells. Overexpression of pro-inflammatory cytokines IL-6 and IL-23 stimulated STAT3 phosphorylation in Treg cells. This study suggests that hyperphosphorylation of STAT3 impairs the proliferation, suppression and cytokine secretion of Treg cells, while inhibiting the phosphorylation of STAT3 restores these functions. These findings clarify the role of STAT3 in the pathogenesis of URSA and provide new ideas for the treatment of URSA.

// Xiao-Qian Fu 1 , Jun-Ying Cai 2 , Qian-Yi Huang 1 , Dong-Ju Li 3 , Ning Li 3 and Mu-Jun Li 1 1 Department of Reproductive Center, First Affiliated Hospital of Guangxi Medical University, Guangxi, China 2 Department of Reproductive Center, Maternal and Child Health Hospital and Obstetrics and Gynecology Hospital of Guangxi Zhuang Autonomous Region, Guangxi, China 3 Guangxi Medical University, Guangxi, China Correspondence to: Mu-Jun Li, email: lmj1699@163.com Keywords: interleukin-17; prednisone; interleukin-10; Treg cells; Th17 cells Received: May 18, 2017 Accepted: October 04, 2017 Published: October 31, 2017 ABSTRACT The objective of this study was to investigate alterations in human first-trimester decidual immune cells (DICs) and relevant cytokines after treatment with prednisone. Decidual lymphocytes were treated with prednisone alone, cytokines alone or the combination of prednisone and cytokines. Levels of STAT3, STAT5, RORC and FOXP3 mRNA were assayed using quantitative real-time PCR, proportions of CD4 + T helper 17 (Th17) and CD4 + T regulatory (Treg) cells were measured using flow cytometry, and concentrations of interleukin (IL)-17A and IL-10 were determined using enzyme-linked immunosorbent assay. After treatment with prednisone alone, levels of STAT5 and FOXP3 mRNA were significantly higher than in untreated control cells (both P < 0.01), while levels of RORC mRNA were significantly lower than in controls ( P < 0.05). Levels of STAT3 mRNA did not vary significantly with treatment. After treatment with prednisone alone, proportions of Th17/CD4 + cells and levels of IL-17A were significantly lower than in control cells, and proportions of Treg/CD4 + cells and levels of IL-10 significantly higher than in controls (all P < 0.01). Our results suggest that prednisone may improve pregnancy outcomes by restoring immunological homeostasis through up-regulation of STAT5 and FOXP3, induction of DIC differentiation into Treg cells, inhibition of DIC differentiation into Th17 cells, reduction of IL-17A secretion and induction of IL-10 secretion.

Objective Repeated implantation failure (RIF) has been shown related to maternal immune imbalance. Many studies suggested that prednisone promoted the Th17/Treg balance shift to the direction of immune tolerance. Our study aimed to evaluate the role of prednisone in Th17/Treg balance and pregnancy outcome in RIF patients. Study design and main outcome measures Peripheral blood of healthy fertile controls and RIF patients were collected at the late proliferation phase. The population of Treg and Th17 cells, the expression of Foxp3 and RORC mRNA and the concentration of IL-17A, IL-23 and IL-10 were detected by flow cytometry, qRT-PCR and enzyme-linked immunosorbent assay. RIF patients were given oral prednisone 10 mg daily from the late proliferation phase of the cycle before FET. After one month of treatment, the above immune indicators were tested, and natural cycle frozen embryo transfer was performed. Results The Treg cells proportion and IL-10 concentration in peripheral blood of RIF patients was lower than that of NF group, while the proportion of Th17 cells and concentration of proinflammatory cytokine were significantly higher. After prednisone treatment, the indicators related to immune tolerance increased significantly. Five out of 19 RIF patients were successful pregnancy after FET, in which, one had an early miscarriage and four live births. No pregnancy complications and fetal abnormalities were observed. Conclusions We report the beneficial effect of prednisone on RIF patients. The underlying mechanism may attribute to shift the Treg/Th17 immune balance to a Treg bias, and enhance embryo implantation, ultimately improve pregnancy outcomes.

Background ATPase family, AAA+ domain containing 2 (ATAD2) is also known as AAA+ nuclear coregulator cancer-associated protein or PRO2000. ATAD2 has been reported as a prognostic factor in different cancer types, but the association between ATAD2 high expression and survival is still unclear. Thereby, this meta-analysis was performed to evaluate the prognostic value of ATAD2 high expression in human cancers. Methods All of the studies included were retrieved from PubMed, EMBASE, and Cochrane Library electronic databases. The clinical outcomes were evaluated by calculating hazard ratio (HR) with their 95% confidence interval (CI). Results Thirteen studies including 2689 patients were eligible for this analysis. The pooled results showed that ATAD2 over-expression was significantly associated with shorter overall survival (OS) (HR = 2.32, 95% CI = 1.77-3.02), as well as shorter recurrence-free survival (RFS), disease-free survival (DFS), and disease-specific survival (DSS) (HR = 1.83, 95% CI = 1.51-2.23) among human cancers. Subgroup analyses for OS were implemented in terms of region, tumor type, and sample size and the results were coincident with overall pooled results. Begg funnel plot and Egger test showed the presence of publication bias for OS. Sensitivity analysis indicated that both results were not affected for removing any study. Conclusion ATAD2 would be likely to act as a prognostic biomarker for the patients of different cancer types and provide a guide on clinical treatment. Prospective clinical studies are needed to support these findings.

Unexplained recurrent spontaneous abortion (URSA) is a common complication of pregnancy. Although tolerance of the maternal immune system is considered to be essential for a normal pregnancy, the precise mechanism underlying the pathogenesis of URSA remains to be fully elucidated, albeit it is known to involve inflammation. Here, we examine the relationship between the expression of inflammatory cytokines and the activation of downstream signaling pathways in URSA patients. Decidual and peripheral blood samples were collected from 30 URSA patients and from 30 women with normal early pregnancies. Western blot analysis was used to measure the expression levels of signal transducers and activators of transcription 3(STAT3), phosphorylated STAT3(p-STAT3), and interleukin-17 receptor(IL-17R) in the decidual samples. Enzyme-linked immunosorbent assay was used to assess the levels of IL-17, IL-10, IL-6, and IL-23 in the peripheral blood and decidual samples. In the URSA patients, the IL-10 expression levels were lower than those in the control subjects (P

Platelet-activating factor (PAF) is a unique and novel signaling phospholipid that has pleiotropic biologic properties in addition to platelet activation. Recent studies show that this novel compound plays a significant role in male reproduction and sperm function. PAF binds surface special receptors inducing the formation of inositol triphosphate (IP3) and diacylglycerol (DAG) and increasing intracellular calcium. The concentrations of sperm-derived PAF may help predict sperm motility and fertilization potential, which may serve as a valuable marker for assessing male fertility. Exogenous PAF can improve sperm motility, acrosome reaction and pregnancy rates in human intrauterine inseminations.